History

Generally, lithium nephrotoxicity will occur within a month of onset of use of the drug, manifested predominantly by polyuria and polydipsia. The onset of these symptoms may also occur in the presence of accelerating dose regimens. Initially, these symptoms are reversible but may become permanent with long-term use and/or chronically high serum lithium levels. When acute kidney injury occurs in the setting of lithium toxicity, the patients generally will exhibit other signs of lithium toxicity, such as obtundation. In particular, elderly patients with acute kidney injury may develop delirium, with confusion, tremors, and ataxia.^[25]

Polyuria

Polyuria, defined as a 24-hour urine output of greater than 3 L, is the most common complication in an otherwise asymptomatic patient who has a plasma lithium level consistent with therapeutic dosing.^[26]Patients may develop polydipsia. In one case report of persistent lithium-induced nephrogenic diabetes insipidus, the patient drank 20-40 glasses of water per day.

Nocturia can be a useful marker of polyuria. Up to 68% of patients report at least 1 urination episode per night.

Physical

Patients with lithium nephrotoxicity may exhibit signs of modest volume depletion, including orthostatic hypotension, tachycardia, and dry mouth. With severe dehydration, patients will show evidence of hypernatremia, including altered mental status.

Signs of volume depletion - Hypotension, orthostasis, tachycardia, and dry mouth
Altered mental status.
Occasional signs of hypothyroidism, including impaired reflexes and bradycardia
Signs of cardiotoxicity, including cardiac conduction blockade, SA node dysfunction, T wave flattening and inversion, and cardiovascular collapse

Differential Diagnoses

Hedya SA, Avula A, Swoboda HD. Lithium Toxicity. BMC Nephrol. 2020 Jan. 19 (1):305. [QxMD MEDLINE Link]. [Full Text].
Baird-Gunning J, Lea-Henry T, Hoegberg LCG, Gosselin S, Roberts DM. Lithium Poisoning. J Intensive Care Med. 2017 May. 32 (4):249-263. [QxMD MEDLINE Link].
Nielsen J, Kwon TH, Christensen BM, et al. Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus. Semin Nephrol. 2008 May. 28(3):227-44. [QxMD MEDLINE Link].
Mu J, Johansson M, Hansson GC, et al. Lithium evokes a more pronounced natriuresis when administered orally than when given intravenously to salt-depleted rats. Pflugers Arch. 1999 Jul. 438(2):159-64. [QxMD MEDLINE Link].
Nielsen J, Kwon TH, Frokiaer J, et al. Lithium-induced NDI in rats is associated with loss of alpha-ENaC regulation by aldosterone in CCD. Am J Physiol Renal Physiol. 2006 May. 290(5):F1222-33.
Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis. 2005 Apr. 45(4):626-37.
Stone KA. Lithium-induced nephrogenic diabetes insipidus. J Am Board Fam Pract. 1999 Jan-Feb. 12(1):43-7. [QxMD MEDLINE Link].
Thompson CJ, France AJ, Baylis PH. Persistent nephrogenic diabetes insipidus following lithium therapy. Scott Med J. 1997 Feb. 42(1):16-7.
Rojek A, Nielsen J, Brooks HL, et al. Altered expression of selected genes in kidney of rats with lithium-induced NDI. Am J Physiol Renal Physiol. 2005 Jun. 288(6):F1276-89.
Walker RJ, Weggery S, Bedford JJ, et al. Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers. Kidney Int. 2005 Jan. 67(1):291-4.
Li Y, Shaw S, Kamsteeg EJ, et al. Development of lithium-induced nephrogenic diabetes insipidus is dissociated from adenylyl cyclase activity. J Am Soc Nephrol. 2006 Apr. 17(4):1063-72. [QxMD MEDLINE Link].
Nielsen J, Hoffert JD, Knepper MA, et al. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci U S A. 2008 Mar 4. 105(9):3634-9. [QxMD MEDLINE Link]. [Full Text].
Marples D, Frokiaer J, Knepper MA, et al. Disordered water channel expression and distribution in acquired nephrogenic diabetes insipidus. Proc Assoc Am Physicians. 1998 Sep-Oct. 110(5):401-6. [QxMD MEDLINE Link].
Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis. 1987 Nov. 10(5):329-45. [QxMD MEDLINE Link].
Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol. 2000 Aug. 11(8):1439-48. [QxMD MEDLINE Link].
Gill J, Singh H, Nugent K. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy. 2003 Jun. 23(6):811-5.
Davis J, Desmond M, Berk M. Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification. BMC Nephrol. 2018 Nov 3. 19 (1):305. [QxMD MEDLINE Link]. [Full Text].
Paw H, Slingo ME, Tinker M. Late onset nephrogenic diabetes insipidus following cessation of lithium therapy. Anaesth Intensive Care. 2007 Apr. 35(2):278-80. [QxMD MEDLINE Link].
Van Alphen AM, Bosch TM, Kupka RW, Hoekstra R. Chronic kidney disease in lithium-treated patients, incidence and rate of decline. Int J Bipolar Disord. 2021 Jan 4. 9 (1):1. [QxMD MEDLINE Link]. [Full Text].
Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 Aug 1. 386 (9992):461-8. [QxMD MEDLINE Link]. [Full Text].
Bocchetta A, Ardau R, Fanni T, Sardu C, Piras D, Pani A, et al. Renal function during long-term lithium treatment: a cross-sectional and longitudinal study. BMC Med. 2015 Jan 21. 13:12. [QxMD MEDLINE Link].
Clos S, Rauchhaus P, Severn A, Cochrane L, Donnan PT. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry. 2015 Dec. 2 (12):1075-83. [QxMD MEDLINE Link].
Aprahamian I, Santos FS, dos Santos B, Talib L, Diniz BS, Radanovic M, et al. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry. 2014 Jul. 75(7):e672-8. [QxMD MEDLINE Link].
Rej S, Herrmann N, Shulman K, Fischer HD, Fung K, Harel Z, et al. Lithium Use, but Not Valproate Use, Is Associated With a Higher Risk of Chronic Kidney Disease in Older Adults With Mental Illness. J Clin Psychiatry. 2017 Sep/Oct. 78 (8):e980-e985. [QxMD MEDLINE Link].
Hlaing PM, Isoardi KZ, Page CB, Pillans P. Neurotoxicity in chronic lithium poisoning. Intern Med J. 2020 Apr. 50 (4):427-432. [QxMD MEDLINE Link].
Robertson GL. Differential diagnosis of polyuria. Annu Rev Med. 1988. 39:425-42. [QxMD MEDLINE Link].
Rej S, Segal M, Low NC, Mucsi I, Holcroft C, Shulman K, et al. The McGill Geriatric Lithium-Induced Diabetes Insipidus Clinical Study (McGLIDICS). Can J Psychiatry. 2014 Jun. 59(6):327-34. [QxMD MEDLINE Link]. [Full Text].
Janowsky DS, Soares J, Hatch JP, et al. Lithium effect on renal glomerular function in individuals with intellectual disability. J Clin Psychopharmacol. 2009 Jun. 29(3):296-9. [QxMD MEDLINE Link].
Farres MT, Ronco P, Saadoun D. Chronic lithium nephropathy: MR imaging for diagnosis. Radiology. 2003. 229:570-4. [QxMD MEDLINE Link].
Roque A, Herédia V, Ramalho M, de Campos R, Ferreira A, Azevedo R, et al. MR findings of lithium-related kidney disease: preliminary observations in four patients. Abdom Imaging. 2011 Jun 30. [QxMD MEDLINE Link].
Wilting I, Baumgarten R, Movig KL, et al. Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration. Eur J Pharmacol. 2007 Jul 2. 566(1-3):50-7. [QxMD MEDLINE Link].
Bailey AR, Sathianathan VJ, Chiew AL, Paterson AD, Chan BS, Arora S. Comparison of intermittent haemodialysis, prolonged intermittent renal replacement therapy and continuous renal replacement haemofiltration for lithium toxicity: a case report. Crit Care Resusc. 2011 Jun. 13(2):120-2. [QxMD MEDLINE Link].
Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, Leader JP, et al. Lithium-induced Nephrogenic Diabetes Insipidus: Renal Effects of Amiloride. Clin J Am Soc Nephrol. 2008. epub ahead of print:[QxMD MEDLINE Link]. [Full Text].
Gordon CE, Vantzelfde S, Francis JM. Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus. N Engl J Med. 2016 Nov 17. 375 (20):2008-2009. [QxMD MEDLINE Link]. [Full Text].
Macau RA, da Silva TN, Silva JR, Ferreira AG, Bravo P. Use of acetazolamide in lithium-induced nephrogenic diabetes insipidus: a case report. Endocrinol Diabetes Metab Case Rep. 2018. 2018:[QxMD MEDLINE Link]. [Full Text].
de Groot T, Doornebal J, Christensen BM, Cockx S, Sinke AP, Baumgarten R, et al. Lithium-induced NDI: acetazolamide reduces polyuria but does not improve urine concentrating ability. Am J Physiol Renal Physiol. 2017 Sep 1. 313 (3):F669-F676. [QxMD MEDLINE Link].
Trepiccione F, Christensen BM. Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings. J Nephrol. 2010 Nov-Dec. 23 Suppl 16:S43-8. [QxMD MEDLINE Link].
Schou M. Forty years of lithium treatment. Arch Gen Psychiatry. 1997 Jan. 54(1):9-13; discussion 14-5. [QxMD MEDLINE Link].
Schoot TS, Molmans THJ, Grootens KP, Kerckhoffs APM. Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy. Eur Neuropsychopharmacol. 2020 Feb. 31:16-32. [QxMD MEDLINE Link].

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Author

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Coauthor(s)

Clifford C Dacso, MD, MPH, MBA John S Dunn Sr Research Chair, The Methodist Hospital Research Institute; Distinguished Research Professor, University of Houston

Clifford C Dacso, MD, MPH, MBA is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Anil Kumar Mandal, MD Clinical Professor, Department of Internal Medicine, Division of Nephrology, University of Florida College of Medicine

Anil Kumar Mandal, MD is a member of the following medical societies: American College of Clinical Pharmacology, American College of Physicians, American Society of Nephrology, Central Society for Clinical and Translational Research

Disclosure: Nothing to disclose.

Mark D T Tran, MD

Mark D T Tran, MD is a member of the following medical societies: American Academy of Family Physicians

Disclosure: Nothing to disclose.

Lithium Nephropathy Clinical Presentation

History

Polyuria

Physical

References

Tables

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